PROJECT SUMMARY Asthma exacerbations affect over half of children ever diagnosed with asthma and cause an immense economic burden. Minority children with asthma living in urban areas are particularly affected by acute asthma episodes, which result in missed school days and lowered academic achievement. Studies have consistently identified environmental pollutants, such as particulate matter (PM), as triggers of asthma exacerbations, yet the exact mechanisms are unclear. Epigenetic modifications, including changes in extracellular vesicles (EVs) and their encapsulated microRNA, may be a mechanism underlying PM-induced asthma morbidity in children diagnosed with asthma. The lack of informative yet non-invasive biomarkers that can identify early adverse health effects in children exposed to high levels of asthma-triggering pollutants curbs opportunities for effective prevention and management. To address this gap, my goal is to identify novel mechanistic biomarkers in saliva, a readily available biofluid, that reflect effects of environmental exposures and can identify children at risk for asthma exacerbations. I will leverage research on EVs in asthma and their roles in saliva as markers of systemic inflammation. Saliva EVs (sEVs) are an emerging and exciting field for noninvasive diagnostic applications, for a majority of compounds found in blood are also present in saliva. Moreover, the diverse components in saliva (such as EVs) can reflect virtually the entire spectrum of both normal and disease states. Saliva-based diagnostics are less invasive, less expensive, and present less risk to both the patient and health care provider than current methodologies. Yet to date, no studies have been conducted to identify the potential of sEVs as a biomarker of effect to PM exposure and biomarker of asthma exacerbations. To achieve this goal, I will conduct a study that leverages the unique resources of the School Inner-City Asthma Study, a study of children with asthma (n=300) that has saliva collection, extensive exposure data, and clinical asthma measures. Concentration of PM and its components outside each subject?s home will be estimated using a previously validated spatiotemporal model. I hypothesize that sEV number and sEV- encapsulated microRNAs reflect levels of recent (1-2 day) ambient PM exposure (Aim 1, prospective analysis) and that sEV number and their enclosed microRNAs are associated with morbidity outcomes among children with asthma (Aim 2, cross-sectional analysis). I will further use advanced statistical modeling to integrate sEV biomarkers on the paths linking exposure and asthma exacerbations (Exploratory Aim 3). This research addresses several NIEHS Strategic Plan goals including: ?Identify and understand?biological pathways ? to enable the development of applicable prevention ? strategies? (Goal 1), and ??understand the disproportionate risks of disease?? (Goal 6). In conclusion, this research will provide a new, noninvasive tool to measure the burden of adverse air pollution exposures and will provide insight into the role of EVs in asthma.